Genetic studies indicate that the E4 allele of apolipoprotein E (apoE) is a major risk factor for Alzheimer's disease (AD) while the presence of the E2 allele may be neuroprotective. ApoE is expressed by glial cells in the central nervous system (CNS) and at even higher levels in the setting of injury. Through little is known about the biological role of apoE in the CNS, data indicate the apoE-containing lipoproteins can alter neurite morphology of neurons derived from both the peripheral nervous system as well as the CNS. Human apoE3 can increase neurite extension whereas apoE4 has little effect or decreases extension. Importantly, the effects of apoE, can increase neurite extension whereas apoE4 has either little effect. The examined to date are mediated through the low density lipoprotein receptor-related protein (LRP). LRP is a large, multifunctional cell surface receptor which is expressed by CNS neurons and mediates endocytosis of several ligands including apoE-containing lipoproteins. Preliminary data also suggest an important role for LRP to axonal outgrowth in vivo. It is hypothesized that LRP mediates the biological effects of apoE on CNS neurons. Thus understanding the normal role of LRP in the CNS as well as the mechanism of isoform-specific differences in apoE=LRP effects may provide insight into AD pathogenesis. In this proposal, the applicants will pursue (1) the biological functions of LRP, (2) the importance of apoE-LRP interactions in vitro and in vivo, and (3) the cell biological processes mediating isoform-specific effects of apoE on CNS neurons. The specific aims are as follows: 1. To determine whether apoE isoforms differentially influence neurite outgrowth and cell survival in primary culture of CNS neurons through LRP. 2. To determine the effects of primary culture of CNS neurons through LRP inhibitor and anti-LRP antibodies on developing CNS neurites in vitro and in vivo. 3. To examine the expression of apoE, LRP, and other molecules potentially relaxant to the effects of apoE (LDL, receptor and VLDL receptor) in mature rat brain. 4. To determine the molecular mechanism (s) by which apoE/LRP responsible for their interactions. These studies should provide nw insights into the normal function of apoE and LRP in the CNS and pathogenesis of AD.